This is an R01 renewal proposal to study the genetics of opioid dependence (OD) and related phenotypes, using a multifaceted approach. An important genetic contribution to risk for OD and related phenotypes is supported by clinical genetic data and by our first round of linkage results. The major purpose of this proposal is to identify specific risk alleles at loci predisposing to OD and related traits, the goals are to collect a set of 900 OD cases and 900 controls, and also to use cases as a basis for the recruitment of additional small nuclear families (SNFs) when possible. The resulting sample based on OD affection will have sufficient power to identify linkage disequilibrium with trait under reasonable assumptions of genetic heterogeneity. The clinical work will take place at two university-based programs, (Yale Univ. School of Medicine/APT Foundation and Univ. CT Health Center), and the laboratory and statistical work will be performed at Yale, Boston University School of Medicine, and the Southwest Foundation for Biomedical Research. Affection will be defined according to DSM-IV diagnostic criteria, ascertained using the Semi- Structured Assessment for Drug Dependence and Alcoholism (SSADDA). This computerized instrument, based on the SSAGA, was developed during the previous grant period. We have implemented an extensive program to assure the quality of the detailed set of clinical data collected and have demonstrated that the diagnoses obtained are highly reliable. This will continue a large-scale study of OD gene mapping, which is one of the first to include substantial (>30%) African-American representation. Results from the first iteration of the project support our ability to complete this ambitious research program successfully. This research program will also create an extensive resource for use by future investigators. The project will build on the successes of the first five-year SNF gene mapping project led by Drs. Gelernter and Kranzler (which has already identified two lod scores >3 for OD-related traits), and will provide information that will, eventually, substantially increase our understanding of the mechanisms of OD, and may be expected to lead to new ways to address this pervasive societal problem both through prevention and treatment.